PROJECT SUMMARY Preterm birth is a significant global health challenge as a leading cause of infant mortality and costly long-term morbidity. Rates of preterm birth in the U.S. have increased in recent decades for reasons that remain uncertain. The recent escalation in preterm births in Puerto Rico is especially alarming, where rates have increased from just above the U.S. average (12%) in 1997 to nearly 18% in 2009. While known risk factors for preterm birth have failed to account for this increase, there is growing evidence that environmental factors may play a key role. However, these factors remain understudied and underappreciated. The proposed project will apply state-of-the-art molecular epidemiological methods to a prospective cohort study of over 1,200 live births designed to explore environmental, clinical, demographic, behavioral and other factors that contribute to preterm birth risk in Puerto Rico. The project also aims to provide much needed information on the potential mechanistic pathways involved in preterm birth as it relates to environmental factors, and data on important predictors of phthalate exposure among pregnant women. Phthalates were chosen as the primary pollutants of interest because they are common contaminants of Superfund sites in Puerto Rico and elsewhere (several phthalates are on the ATSDR Substance Priority List), and recent studies show widespread exposure to phthalates in the U.S. population. In our preliminary work and in recent studies by others, multiple phthalates have been associated with preterm birth, reduced gestational age, and other adverse impacts potentially linked with preterm birth such as oxidative stress, inflammation, and endocrine disruption. Our preliminary data also suggests elevated exposure to certain phthalates in Puerto Rico compared to the U.S. Using data and samples generated by recruitment efforts of the Human Subjects and Sampling Core (Core C) and the Data Management integration provided by Core D, we will collect detailed questionnaire data, clinical information, and measure phthalate metabolites in urine samples collected from pregnant women at multiple time points in pregnancy. We will evaluate phthalate metabolite levels for associations with residence, water sources, water phthalate contamination, diet, activities, and product use to identify determinants of high exposure and opportunities for exposure reduction strategies. Using innovative statistical methods, we will assess the association between exposure to phthalates and risk of preterm birth, both as individual chemicals and as phthalate mixtures. We will also explore relationships between phthalate exposure and biomarkers of oxidative stress, inflammation, and endocrine disruption measured at multiple times during pregnancy to provide data on biologic pathways that may link environmental exposures with early parturition. The proposed study will provide much needed information on preterm birth risk factors in Puerto Rico and a rich resource for future investigations and follow-up. Identifying modifiable environmental risk factors for preterm birth could have huge public health impact since interventions aimed at preventing preterm birth to date remain largely ineffective.